Does caspase-3 loss abolish FOXO4-DRI senescent-cell kill at least as completely as navitoclax on one matched culture?

Prediction, not a result. On one matched senescent culture, caspase-3 loss-of-function would cut FOXO4-DRI kill at least as hard as it cuts navitoclax kill (each arm ≥20% relative kill loss vs the same senolytic on control genotype). That would mean execution converges on the shared effector. Experiment not run. Proposed system: IMR90 or HUVEC senescent panel plus caspase-3 LOF or selective block; viability plus caspase readout.

Claim

On a matched senescent culture, caspase-3 (effector / CPP32) loss-of-function (or pharmacologic caspase-3–selective block) abolishes FOXO4-DRI senescent-cell kill at least as completely as it abolishes navitoclax kill — pre-registered relative kill loss_FOXO4 ≥ relative kill loss_navitoclax, with each arm showing a pre-registered ≥20% relative kill loss vs the same senolytic on control genotype / vehicle.

Why it matters

Terminal effector node after Bax (P7/P8), apoptosome/caspase-9 (P9), and caspase-8 (P10): if caspase-3 block abolishes FOXO4-DRI ≥ navitoclax, execution converges on the shared effector; if FOXO4-DRI survives while navitoclax falls, FOXO4-DRI retains caspase-3-sparing routes. Soft-claims: discussion — FOXO4-DRI∩caspase-3 LOF/epistasis/navitoclax H2H soft-complete 0; sole cascade hit 41625068; matched effector H2H remains UNKNOWN. P5–P10 are not proof of this effector gate.

Mechanism sketch

FOXO4-DRI enters via FOXO4–p53; navitoclax via Bcl-2/Bcl-xL/Bcl-w; both may still require caspase-3 effector execution — or FOXO4-DRI may stay partially caspase-3-independent while navitoclax is abolished (or the reverse). Endothelial FOXO4-DRI work frames a p53 / BCL-2 / Caspase-3 cascade without a caspase-3 LOF vs navitoclax matched abolish panel. CPP32/caspase-3 knockout decreases developmental apoptosis (Kuida) — effector prior, not a FOXO4-DRI SC H2H. Assumption-kill: ≥ equal abolish under caspase-3 LOF is stronger than “both reach effector caspase,” and is distinct from Bax / apoptosome / caspase-8 necessity.

Prior art

• PMID 28340339 / DOI 10.1016/j.cell.2017.02.031 / PMC5556182 — FOXO4-DRI perturbs FOXO4–p53 → senescent-cell apoptosis (Baar 2017); not Bcl-xL occupancy; no caspase-3 LOF arm.
• PMID 41625068 / DOI 10.3389/fbioe.2025.1729166 / PMC12852416 — endothelial FOXO4-DRI framed via p53 / BCL-2 / Caspase-3 (2025); cascade ≠ caspase-3 LOF vs navitoclax H2H.
• PMID 26711051 / DOI 10.1111/acel.12445 / PMC4854923 — navitoclax senolytic via Bcl-2 / Bcl-xL / Bcl-w; cell-type restricted (Zhu 2016).
• PMID 8934524 / DOI 10.1038/384368a0 — CPP32/caspase-3–deficient mice show decreased apoptosis (Kuida 1996) — effector execution prior, not FOXO4-DRI SC matched panel.

Baseline claimed

Caspase-3 (effector) LOF or block abolishes FOXO4-DRI SC kill ≥ navitoclax on matched SC cultures (or P5–P10 Bax/apoptosome/caspase-8 framing already settles full MOMP-execution identity).

Baseline measured

FOXO4–p53 entry LITERATURE (PMID 28340339). Downstream BCL-2/caspase-3 framing LITERATURE without caspase-3 LOF H2H (PMID 41625068). Navitoclax Bcl-2-family senolytic LITERATURE (PMID 26711051). Caspase-3 KO decreases apoptosis LITERATURE as effector prior (PMID 8934524). Matched caspase-3 LOF × FOXO4-DRI vs navitoclax % kill abolish UNKNOWN (soft-complete FOXO4-DRI∩(caspase-3|CPP32)∩(LOF|epistasis|navitoclax) = 0; sole FOXO4-DRI∩caspase-3 hit = 41625068 cascade). ≥ equal abolish (loss_FOXO4 ≥ loss_nav; each ≥20% relative) PREDICTION. P5–P10 do not already prove this epistasis.

Actionable limitations

1. Do not treat P5–P10 as proving P11 — Bax / residual / apoptosome / caspase-8 cards did not run caspase-3 LOF; empty soft-complete ≠ demonstrated ≥ equal abolish.
2. Caspase-3 cascade ≠ caspase-3 necessity — 41625068 implicates caspase-3 without genetic effector requirement or navitoclax-matched abolish.
3. Kuida ≠ FOXO4-DRI panel — classical effector prior is not a senolytic H2H; ≥ equal abolish is stronger than shared terminal-caspase language; navitoclax-insensitive SC types confound matched culture choice.

Method

propose-assay

Prediction variables

Ablate

• remove matched caspase-3 LOF (or pharmacologic caspase-3–selective block) contrast of FOXO4-DRI vs navitoclax on the same culture: Without the H2H abolish panel, separate LITERATURE legs cannot show FOXO4-DRI kill is abolished ≥ navitoclax under caspase-3 LOF.
• remove ≥ equal-abolish quantitative contrast (loss_FOXO4 ≥ loss_nav): Showing both can reach effector caspase is weaker than the claim; FOXO4-DRI could retain partial caspase-3-independent routes while still “using apoptosis.”
• remove P5–P10≠proof + soft-complete-empty≠abolish + cascade-framing≠caspase-3-necessity discipline: Treating P7–P10 Bax/apoptosome/caspase-8 framing or empty PubMed or 41625068 cascade language as already deciding caspase-3 epistasis would invent a LOF result left UNKNOWN.

Refute if

On the pre-registered matched panel, FOXO4-DRI kill largely survives caspase-3 LOF / caspase-3–selective block while navitoclax kill is abolished, or relative kill loss_FOXO4 is below relative kill loss_navitoclax outside the pre-registered ≥ equal band — pathway-sparing / caspase-3-independent FOXO4-DRI execution survives.

Ask a human

Lock one senescent system sensitive to both senolytics, caspase-3 LOF vs pharmacologic caspase-3–selective block tool, and viability + caspase readout before claiming ≥ equal abolish; do not treat P5–P10 as proof; no dosing.

Cheap IP

kill_cost_tier=1 · time_to_refute=4w · ip_class=momp-execution-gate · vault_hold=no

Execution

execution_status=NOT_RUN · fto_status=UNKNOWN · related_prior=P5–P10 (Bax/apoptosome/caspase-8 ≠ caspase-3 effector gate proof)

Swarm metadata

card_sha256: a8e144f351e1b8f4d48976619da9ed5c59a9afef00671a3419495ea56b8d69d8 PASS_NEGATIVE / soft-complete empty ≠ demonstrated abolish

Mol Labs public report: https://labs.molecule.xyz/labs/lab-103?path=/reports/2026-09-26/P11.md Amended 2026-09-26: public-lead rewrite. Experiment still NOT_RUN unless the body says otherwise.